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Plasmonic nanosensors with inverse sensitivity by means of enzyme-guided crystal growth

A Corrigendum to this article was published on 23 January 2018

An Addendum to this article was published on 23 January 2018

This article has been updated


Lowering the limit of detection is key to the design of sensors needed for food safety regulations1,2, environmental policies3,4,5 and the diagnosis of severe diseases6,7,8,9,10. However, because conventional transducers generate a signal that is directly proportional to the concentration of the target molecule, ultralow concentrations of the molecule result in variations in the physical properties of the sensor that are tiny, and therefore difficult to detect with confidence. Here we present a signal-generation mechanism that redefines the limit of detection of nanoparticle sensors by inducing a signal that is larger when the target molecule is less concentrated. The key step to achieve this inverse sensitivity is to use an enzyme that controls the rate of nucleation of silver nanocrystals on plasmonic transducers. We demonstrate the outstanding sensitivity and robustness of this approach by detecting the cancer biomarker prostate-specific antigen down to 10−18 g ml−1 (4 × 10−20 M) in whole serum.

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Figure 1: Scheme of the proposed signal-generation mechanism by means of enzyme-guided crystal growth.
Figure 2: Inverse sensitivity in plasmonic nanosensors.
Figure 3: TEM and XEDS analysis of silver-coated gold nanostars.
Figure 4: Immunoassay for the ultrasensitive detection of PSA with GOx-labelled antibodies.

Change history

  • 15 December 2017

    In the version of this Letter originally published, the x and y values of the data points in Fig. 2c were incorrect. The authors have also made some changes to the Supplementary Information: Fig. S9 has been replaced because the x values were incorrect; the value of the carbonate buffer concentration has been corrected to 10 mM; and the sentence on page 2 that read "Subsequently, non-reacted aldehyde sites were blocked with bovine serum albumin (BSA, 0.1 mg/mL) and ethanolamine (10 mM) in bicarbonate buffer for 1 h." has been changed to "When modifying nanostars with antibodies, non-reacted aldehyde sites were blocked with bovine serum albumin (BSA, 0.1 mg/mL) and ethanolamine (10 mM) in bicarbonate buffer for 1 h."

  • 23 January 2018

    Nature Materials 11, 604–607 (2012); published online 27 May 2012; corrected after print 15 December 2017. In the version of this Letter originally published, the x and y values of the data points in Fig. 2c were incorrect. The original and corrected versions are shown below. The authors have also made some changes to the Supplementary Information: Fig.


  1. Batt, C. A. Food pathogen detection. Science 316, 1579–1580 (2007).

    Article  CAS  Google Scholar 

  2. De la Rica, R., Baldi, A., Fernandez-Sanchez, C. & Matsui, H. Single-cell pathogen detection with a reverse-phase immunoassay on impedimetric transducers. Anal. Chem. 81, 7732–7736 (2009).

    Article  CAS  Google Scholar 

  3. Ferber, D. Overhaul of CDC panel revives lead safety debate. Science 298, 732–732 (2002).

    Article  CAS  Google Scholar 

  4. De la Rica, R., Mendoza, E. & Matsui, H. Bioinspired target-specific crystallization on peptide nanotubes for ultrasensitive Pb ion detection. Small 6, 1753–1756 (2010).

    Article  CAS  Google Scholar 

  5. Li, D., Wieckowska, A. & Willner, I. Optical analysis of Hg(2+) ions by oligonucleotide-gold-nanoparticle hybrids and DNA-based machines. Angew. Chem. Int. Ed. 47, 3927–3931 (2008).

    Article  CAS  Google Scholar 

  6. Giljohann, D. A. & Mirkin, C. A. Drivers of biodiagnostic development. Nature 462, 461–464 (2009).

    Article  CAS  Google Scholar 

  7. Rissin, D. M. et al. Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nature Biotechnol. 28, 596–599 (2010).

    Article  Google Scholar 

  8. Fan, R. et al. Integrated barcode chips for rapid, multiplexed analysisof proteins in microliter quantities of blood. Nature Biotechnol. 26, 1373–1378 (2008).

    Article  CAS  Google Scholar 

  9. Laromaine, A., Koh, L. L., Murugesan, M., Ulijn, R. V. & Stevens, M. M. Protease-triggered dispersion of nanoparticle assemblies. J. Am. Chem. Soc. 129, 4156–4157 (2007).

    Article  CAS  Google Scholar 

  10. Miranda, O. R. et al. Enzyme-amplified array sensing of proteins in solution and in biofluids. J. Am. Chem. Soc. 132, 5285–5289 (2010).

    Article  CAS  Google Scholar 

  11. Aili, D. & Stevens, M. M. Bioresponsive peptide-inorganic hybrid nanomaterials. Chem. Soc. Rev. 39, 3358–3370 (2010).

    Article  CAS  Google Scholar 

  12. Willner, I., Baron, R. & Willner, B. Growing metal nanoparticles by enzymes. Adv. Mater. 18, 1109–1120 (2006).

    Article  CAS  Google Scholar 

  13. Liz-Marzan, L. M. Tailoring surface plasmons through the morphology and assembly of metal nanoparticles. Langmuir 22, 32–41 (2006).

    Article  CAS  Google Scholar 

  14. Pejoux, C., de la Rica, R. & Matsui, H. Biomimetic crystallization of sulfide semiconductor nanoparticles in aqueous solution. Small 6, 999–1002 (2010).

    Article  CAS  Google Scholar 

  15. Kisailus, D., Choi, J. H., Weaver, J. C., Yang, W. J. & Morse, D. E. Enzymatic synthesis and nanostructural control of gallium oxide at low temperature. Adv. Mater. 17, 314–318 (2005).

    Article  CAS  Google Scholar 

  16. Jana, N. R., Gearheart, L. & Murphy, C. J. Evidence for seed-mediated nucleation in the chemical reduction of gold salts to gold nanoparticles. Chem. Mater. 13, 2313–2322 (2001).

    Article  CAS  Google Scholar 

  17. Seo, J. T. et al. Optical nonlinearities of Au nanoparticles and Au/Ag coreshells. Opt. Lett. 34, 307–309 (2009).

    Article  CAS  Google Scholar 

  18. Cardinal, M. F., Rodriguez-Gonzalez, B., Alvarez-Puebla, R. A., Perez-Juste, J. & Liz-Marzan, L. M. Modulation of localized surface plasmon and SERS response in gold dumbbells through silver coating. J. Phys. Chem. C 114, 10417–10423 (2010).

    Article  Google Scholar 

  19. Kumar, P. S., Pastoriza-Santos, I., Rodriguez-Gonzalez, B., Garcia de Abajo, F. J. & Liz-Marzan, L. M. High-yield synthesis and optical response of gold nanostars. Nanotechnology 19, 015606 (2007).

    Article  Google Scholar 

  20. Barbosa, S. et al. Tuning size and sensing properties in colloidal gold nanostars. Langmuir 26, 14943–14950 (2010).

    Article  CAS  Google Scholar 

  21. Liu, M. & Guyot-Sionnest, P. Mechanism of silver(I)-assisted growth of gold nanorods and bipyramids. J. Phys. Chem. B 109, 22192–2220 (2005).

    Article  CAS  Google Scholar 

  22. Thaxton, C. S. et al. Nanoparticle-based bio-barcode assay redefines undetectable PSA and biochemical recurrence after radical prostatectomy. Proc. Natl Acad. Sci. USA 106, 18437–18442 (2009).

    Article  CAS  Google Scholar 

  23. Sanchez-Iglesias, A. et al. Synthesis and optical properties of gold nanodecahedra with size control. Adv. Mater. 18, 2529–2534 (2006).

    Article  CAS  Google Scholar 

  24. Roh, K-H., Martin, D. C. & Lahann, J. Biphasic Janus particles with nanoscale anisotropy. Nature Mater. 4, 759–763 (2005).

    Article  CAS  Google Scholar 

  25. Marinakos, S. M., Chen, S. & Chilkoti, A. Plasmonic detection of a model analyte in serum by a gold nanorod sensor. Anal. Chem. 79, 5278–5283 (2007).

    Article  CAS  Google Scholar 

  26. De la Rica, R. & Matsui, H. Urease as a nanoreactor for growing crystalline ZnO nanoshells at room temperature. Angew. Chem. Int. Ed. 47, 5415–5417 (2008).

    Article  CAS  Google Scholar 

  27. Kisailus, D., Schwenzer, B., Gomm, J., Weaver, J. C. & Morse, D. E. Kinetically controlled catalytic formation of zinc oxide thin films at low temperature. J. Am. Chem. Soc. 128, 10276–10280 (2006).

    Article  CAS  Google Scholar 

  28. Tang, Z., Zhang, Z., Wang, Y., Glotzer, S. C. & Kotov, N. A. Self-assembly of CdTe nanocrystals into free-floating sheets. Science 314, 274–278 (2006).

    Article  CAS  Google Scholar 

  29. Aili, D., Selegard, R., Baltzer, L., Enander, K. & Liedberg, B. Colorimetric protein sensing by controlled assembly of gold nanoparticles functionalized with synthetic receptors. Small 5, 2445–2452 (2009).

    Article  CAS  Google Scholar 

  30. DeVries, G. A. et al. Divalent metal nanoparticles. Science 315, 358–361 (2007).

    Article  CAS  Google Scholar 

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B. Rodrı´guez-González is thanked for electron-microscopy analysis. M.M.S. thanks the EPSRC and ERC starting investigator grant ‘Naturale’ for financial support. This research was supported by a Marie Curie Intra European Fellowship within the 7th European Community Framework Programme (R.d.l.R.). L.M.L-M. acknowledges the ERC grant ‘Plasmaquo’ for financial support. L.R-L. acknowledges an FPU scholarship from Ministerio de Educación, Spain. R.A.A-P. acknowledges financial support from CTQ2011-23167 (Ministerio de Economíca y Competitividad, Spain).

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R.d.l.R. elaborated the concept and designed experiments. L.R-L. performed the experiments. M.M.S. and L.M.L-M. supervised the project. All of the authors participated in scientific discussions and wrote the paper.

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Correspondence to Roberto de la Rica or Molly M. Stevens.

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The authors declare no competing financial interests.

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Rodríguez-Lorenzo, L., de la Rica, R., Álvarez-Puebla, R. et al. Plasmonic nanosensors with inverse sensitivity by means of enzyme-guided crystal growth. Nature Mater 11, 604–607 (2012).

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